NEUROACTIVE SUBSTITUTED CYCLOPENT[a]ANTHRACENES AS MODULATORS FOR GABA TYPE-A RECEPTORS

ABSTRACT

The present disclosure is generally directed to neuroactive substituted cyclopent[a]anthracenes as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority benefit of U.S. Provisional PatentApplication Ser. No. 61/783,687, filed on Mar. 14, 2013, the entirecontent of which is incorporated herein by reference.

GOVERNMENT SUPPORT

The claimed subject matter was developed with Government support underNIH Grant #GM47969, awarded by the National Institute of Health.Accordingly, the Government has certain rights in the claimed subjectmatter.

BACKGROUND OF THE DISCLOSURE

The present disclosure is generally directed to novel compounds havingutility as an anesthetic and/or in the treatment of disorders relatingto GABA function and activity. More specifically, the present disclosureis directed to 1,6-cyclo-1,10-secosteroids (cyclopent[a]anthracenes)that are neuroactive and suitable for use as an anesthetic, as well aspharmaceutically acceptable salts thereof, and pharmaceuticalcompositions containing them.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitterof the central nervous system. GABA activates two types of receptors,the inotropic GABA_(A) and the metabotropic GABA_(B) receptor.Activation of the GABA_(B) receptor by GABA causes hyperpolarization anda resultant inhibition of neurotransmitter release. The GABA_(A)receptor subtype regulates neuronal excitability and rapid mood changes,such as anxiety, panic, and stress response. GABA_(A) receptors arechloride ion channels; as a result, activation of the receptor inducesincreased inward chloride ion flux, resulting in membranehyperpolarization and neuronal inhibition. Drugs that stimulate GABA_(A)receptors, such as benzodiazepines and barbiturates, have anticonvulsiveeffects (by reducing neuronal excitability and raising the seizurethreshold), as well as anxiolytic and anesthetic effects.

The effect of certain steroids on GABA_(A) receptors has beenwell-established. As a result, researchers continue to pursue thediscovery and synthesis of neuroactive steroids that may act asanesthetics and/or that may serve to provide treatment for disordersrelated to GABA function. For example, it is now widely accepted thatthe intravenous anesthetic alphaxalone (Compound A, below) causesgeneral anesthesia in humans because it allosterically increaseschloride currents mediated by GABA acting at GABA_(A) receptors in thebrain. However, the various structural features that enable thiscompound to function in the way it does have, to-date, not been fullyunderstood.

In particular, the effect of changing the manner in which the four ringsof neurosteroids are connected and the locations of the substituents onalternatively connected rings is not completely understood. The subjectof this disclosure is new neurosteroid analogues in which thecarbon-carbon bond between positions C₁ and C₁₀ has been abolished and anew carbon-carbon bond between positions C₁ and C₆ has been established(see, e.g., FIG. 1A and FIG. 1B). These compounds are named herein as1,6-cyclo-1,10-secosteroids (cyclopent[a]anthracenes).

In addition to anesthetic properties, neuroactivecyclopent[a]anthracenes may be used to treat disorders related to GABAfunction. For example, neuroactive cyclopent[a]anthracenes may be usedas sedative-hypnotics, exhibiting benzodiazepine-like actions, inducingreduced sleep latency and increased non-REM sleep with only smallchanges in slow wave and REM sleep. Further, drugs that enhance GABAresponses are often used to treat anxiety in humans. Thus, it might beexpected that GABA-potentiating cyclopent[a]anthracenes would exhibitanxiolytic effects. Neuroactive cyclopent[a]anthracenes may also be usedto treat depression, given that accumulating evidence suggests thatpatients with major depression have decreased levels of GABAergicneurosteroids and that certain treatments for depression alter levels ofthese neurosteroids. Although GABA is not typically thought to play acritical role in the biology of depression, there is evidence that lowGABAergic activity may predispose one to mood disorders. Finally,inhibition of NMDA receptors and enhancement of GABA_(A) receptorsappear to play important roles in mediating the acute effects of ethanolin the nervous system, while related studies suggest that GABAergicneurosteroids may be involved in some of the pharmacological effects ofethanol and that neuroactive neurosteroids may be useful in treatingethanol withdrawal. Thus, cyclopent[a]anthracenes as analogues ofendogenous neurosteroids may be useful for treating these conditions.

In view of the foregoing, it is clear that there are a number ofpotentially advantageous uses for cyclopent[a]anthracenes. As a result,there is a continuing need for the further synthesis and understandingof new neuroactive cyclopent[a]anthracenes, particularly those havingutility as an anesthetic and/or in the treatment of a disorder relatingto GABA function and activity.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure is directed to a compound having astructure of Formula (I):

or a pharmaceutically acceptable salt thereof;wherein:R₁ is H, ═O, ═CHCN, ═CHCO₂R_(z), where R_(z) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-CN, β-OH, β-OR_(y), where R_(y) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(x), where R_(x) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-CN, β-OH, β-OR_(v), where R_(v) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(u), where R_(u) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, —CN, β-OH, β-OR_(s), where R_(s) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₄ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₅ is H, ═O, NH(CH₃)₂, NH(CH₂CH₃)₂, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q),where R_(q) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, CH₂OR_(p), where R_(p) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)R_(o), where R_(o) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)NHR_(n), where R_(n) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂NHR_(m), where R_(m) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, or OR_(l), where R_(l) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₆ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₇ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₈ is H, optionally substituted morpholinyl, or OR_(k), where R_(k) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₉ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl;

R₁₀ is H, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(j), where R_(j) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂OR_(i), where R_(i) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)R_(h), where R_(h) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)NHR_(g), where R_(g) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, or CH₂NHR_(f), where R_(f) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₁₁ is H or C(O)R_(e), where R_(e) is optionally substituted C₁-C₂₀alkyl, optionally substituted C₂-C₂₀ alkenyl, or optionally substitutedC₂-C₂₀ alkynyl; and,

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between, C₁-C₂, C₆-C_(6a), C_(6a)-C₇, or C₉-C₁₀, with theprovisos that when present between: (i) C_(6a)-C₇, R₇ is not present;(ii) C₆-C_(6a), R₇ is not present and either R₅ or R₆ is not present,and, when present, R₅ is other than ═O; (iii) C₁-C₂, R₁ is other than═O, ═CHCN or ═CHCO₂R^(z), and R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w);and, (iv) C₂-C₃, R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w), and R₃ isother than ═O, ═CHCN or ═CHCO₂R_(t).

In another aspect, the present disclosure is directed to a compoundhaving a structure of Formula (II):

or a pharmaceutically acceptable salt thereof;wherein:

R₁ is H, ═O, ═CHCN, ═CHCO₂R_(z), where R_(z) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-CN, α-OH, α-OR_(y), where R_(y) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(x), where R_(x) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-CN, α-OH, α-OR_(v), where R_(v) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(u), where R_(u) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, —CN, α-OH, α-OR_(s), where R_(s) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₄ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₅ is H, ═O, NH(CH₃)₂, NH(CH₂CH₃)₂, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q),where R_(q) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, CH₂OR_(p), where R_(p) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)R_(o), where R_(o) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)NHR_(n), where R_(n) is optionallysubstituted C C₄ alkyl, optionally substituted C₂-C₄ alkenyl, optionallysubstituted C₂-C₄ alkynyl, or optionally substituted aryl, CH₂NHR_(m),where R_(m) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, or OR_(l), where R_(l) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl;

R₆ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₇ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₉ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl;

R₁₀ is H, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(j), where R_(j) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂OR_(i), where R_(i) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)R_(h), where R_(h) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)NHR_(g), where R_(g) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, or CH₂NHR_(f), where R_(f) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₁₁ is H or C(O)R_(e), where R_(e) is optionally substituted C₁-C₂₀alkyl, optionally substituted C₂-C₂₀ alkenyl, or optionally substitutedC₂-C₂₀ alkynyl;

R₁₂ is H, optionally substituted morpholinyl, or OR_(k), where R_(k) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl; and,

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between, C₁-C₂, C₂-C₃, C₆-C_(6a), C_(6a)-C₇, or C₉-C₁₀, withthe provisos that when present between: (i) C_(6a)-C₇, R₇ is notpresent; (ii) C₆-C_(6a), R₇ is not present and either R₅ or R₆ is notpresent, and, when present, R₅ is other than ═O; (iii) C₁-C₂, R₁ isother than ═O, ═CHCN or ═CHCO₂R_(z), and R₂ is other than ═O, ═CHCN or═CHCO₂R_(w); and, (iv) C₂-C₃, R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w),and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t).

The present disclosure is still further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of one or moreof the above-noted cyclopent[a]anthracenes or pharmaceuticallyacceptable salts thereof, and optionally a pharmaceutically acceptablecarrier. The present disclosure also provides kits comprisingcyclopent[a]anthracenes, salts thereof, and/or pharmaceuticalcompositions thereof.

The present disclosure further provides methods of inducing anesthesiain a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of one or more of theabove-noted cyclopent[a]anthracenes, or pharmaceutically acceptablesalts thereof, or a pharmaceutical composition thereof.

The present disclosure further provides methods of treating disordersrelated to GABA function in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of one or more of the above-noted cyclopent[a]anthracenes, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the disorder is selectedfrom the group consisting of insomnia, mood disorders, convulsivedisorders, Fragile X syndrome, anxiety, or symptoms of ethanolwithdrawal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is an exemplary embodiment of a cyclopent[a]phenanthrene.

FIG. 1B is an exemplary embodiment of a cyclopent[a]anthracene.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In accordance with the present disclosure, it has been discovered thatcompounds having certain substituted cyclopent[a]anthracene structuresare neuroactive and are also suitable for use as anesthetics and in thetreatment of disorders associated with GABA function, as well aspharmaceutically acceptable salts thereof. The compounds may be used,for example, as an effective continuous infusion sedative fornon-surgical procedures (e.g., colonoscopy). The compounds also offeradvantages over anesthetics known in the art, such as a lower likelihoodfor bacterial contamination, as well as an improved relationship withsolubilizing agents.

1A. CYCLOPENT[A]ANTHRACENE STRUCTURE

Generally speaking, in one embodiment, the cyclopent[a]anthracene of thepresent disclosure has a tetracyclic, fused ring structure (anembodiment of which is illustrated and discussed in greater detailbelow), wherein the C₈-position of the A ring has a hydroxyl or an estersubstituent in the alpha configuration and the C₃ position has asubstituent attached thereto selected from the group consisting of H,═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, or optionally substitutedC₂-C₄ alkynyl, —CN, β-OH, β-OR_(s), where R_(s) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, and C(O)R_(r),where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl.

More particularly, however, the present disclosure is directed, incertain embodiments, to a cyclopent[a]anthracene having the structure ofFormula (I):

or a pharmaceutically acceptable salt thereof;wherein:

R₁ is H, ═O, ═CHCN, ═CHCO₂R_(z), where R_(z) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-CN, β-OH, β-OR_(y), where R_(y) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(x), where R_(x) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-CN, β-OH, β-OR_(v), where R_(v) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(u), where R_(u) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, —CN, β-OH, β-OR_(s), where R_(s) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₄ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₅ is H, ═O, NH(CH₃)₂, NH(CH₂CH₃)₂, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q),where R_(q) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, CH₂OR_(p), where R_(p) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)R_(o), where R_(o) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)NHR_(n), where R_(n) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂NHR_(m), where R_(m) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, or OR_(l), where R_(l) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₆ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₇ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₈ is H, optionally substituted morpholinyl, or OR_(k), where R_(k) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₉ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl;

-   -   R₁₀ is H, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(j), where R_(j) is        optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄        alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally        substituted aryl, CH₂OR_(i), where R_(i) is optionally        substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,        optionally substituted C₂-C₄ alkynyl, or optionally substituted        aryl, C(O)R_(h), where R_(h) is optionally substituted C₁-C₄        alkyl, optionally substituted C₂-C₄ alkenyl, optionally        substituted C₂-C₄ alkynyl, or optionally substituted aryl,        C(O)NHR_(g), where R_(g) is optionally substituted C₁-C₄ alkyl,        optionally substituted C₂-C₄ alkenyl, optionally substituted        C₂-C₄ alkynyl, or optionally substituted aryl, or CH₂NHR_(f),        where R_(f) is optionally substituted C₁-C₄ alkyl, optionally        substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl,        or optionally substituted aryl;

R₁₁ is H or C(O)R_(e), where R_(e) is optionally substituted C₁-C₂₀alkyl, optionally substituted C₂-C₂₀ alkenyl, or optionally substitutedC₂-C₂₀ alkynyl; and,

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between, C₁-C₂, C₂-C₃, C₆-C_(6e), C_(6e)-C₇, or C₉-C₁₀, withthe provisos that when present between: (i) C_(6a)-C₇, R₇ is notpresent; (ii) C₆-C_(6a), R₇ is not present and either R₅ or R₆ is notpresent, and, when present, R₅ is other than ═O; (iii) C₁-C₂, R₁ isother than ═O, ═CHCN or ═CHCO₂R_(z), and R₂ is other than ═O, ═CHCN or═CHCO₂R_(w); and, (iv) C₂-C₃, R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w),and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t).

As generally defined above, R₁ is H, ═O, ═CHCN, ═CHCO₂R_(z), where R_(z)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-CN, β-CH, β-OR_(y),where R_(y) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl,β-NO₂, spiroepoxy, or C(O)R_(x), where R_(x) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl. In a preferred embodiment, R₁ is H.

As generally defined above, R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-CN, β-OH, β-OR_(v),where R_(v) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl,β-NO₂, spiroepoxy, or C(O)R_(u), where R_(u) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl. In a preferred embodiment, R₂ is H.

As generally defined above, R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, —CN, β-OH, β-OR_(s),where R_(s) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl,β-NO₂, spiroepoxy, or C(O)R_(r), where R_(r) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl. In certain embodiments, R₃ is ═O. In othercertain embodiments, R₃ is spiroepoxy. In other certain embodiments, R₃is β-CN. In other certain embodiments, when a double bond is presentbetween C₂-C₃, R₃ is —CN.

As generally defined above, R₄ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₄ is methyl. R₄ is in the betaconfiguration.

As generally defined above, R₅ is H, ═O, NH(CH₃)₂, NH(CH₂CH₃)₂,CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q), where R_(q) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂OR_(p), where R_(p) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)R_(o), where R_(o) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)NHR_(n), where R_(n) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, CH₂NHR_(m), where R_(m) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, or OR_(l), where R_(l) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In certain embodiments, theoptionally substituted aryl is optionally substituted phenyl ornaphthyl. In a preferred embodiment, R₅ is H.

As generally defined above, R₆ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₆ is H.

As generally defined above, R₇ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₇ is H. In a preferred embodiment,R₇ is in the alpha configuration.

As generally defined above, R₈ is H, optionally substituted morpholinyl,or OR_(k), where R_(k) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl. In certain embodiments, the optionallysubstituted aryl is optionally substituted phenyl or naphthyl. In apreferred embodiment, R₈ is H. R₈ is in the beta configuration.

As generally defined above, R₉ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In other certain embodiments,the optionally substituted alkyl is alkyl aryl, such as alkyl benzyl. Ina preferred embodiment, R₉ is H. R₉ is in the beta configuration.

As generally defined above, R₁₀ is H, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂,CO₂R_(j), where R_(j) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, CH₂OR_(i), where R_(i) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)R_(h), where R_(h) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)NHR_(g), where R_(g) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl, orCH₂NHR_(f), where R_(f) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In a preferred embodiment, R₁₀is H. R₁₀ is in the beta configuration.

As generally defined above, R₁₁ is H or C(O)R_(e), where R_(e) isoptionally substituted C₁-C₂₀ alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀ alkynyl. In one embodiment,R_(e) is optionally substituted C₁-C₁₅ alkyl, preferably optionallysubstituted C₁-C₁₀ alkyl, more preferably optionally substituted C₁-C₄alkyl. In another embodiment, R_(e) is optionally substituted C₁-C₁₅alkenyl, preferably optionally substituted C₁-C₁₀ alkenyl, morepreferably optionally substituted C₁-C₄ alkenyl. In yet anotherembodiment, R_(e) is optionally substituted C₁-C₁₅ alkynyl, preferablyoptionally substituted C₁-C₁₀ alkynyl, more preferably optionallysubstituted C₁-C₄ alkynyl. In a preferred embodiment, R₁₁ is H.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in either a C═C bond between, C₁-C₂, C₂-C₃, C₆-C_(6a),C_(6a)-C₇, or C₉-C₁₀, with the provisos that when present between: (i)C_(6a)-C₇, R₇ is not present; (ii) C₆-C_(6a), R₇ is not present andeither R₅ or R₆ is not present, and, when present, R₅ is other than ═O;(iii) C₁-C₂, R₁ is other than ═O, ═CHCN or ═CHCO₂R_(z), and R₂ is otherthan ═O, ═CHCN or ═CHCO₂R_(w); and, (iv) C₂-C₃, R₂ is other than ═O,═CHCN or ═CHCO₂R_(w), and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t).

In one embodiment, a double bond is present between C₉-C₁₀. In anotherembodiment, a double bond is present between C_(6a)-C₇. In yet anotherembodiment, a double bond is present between C₆-C_(6a). When a doublebond is present between either C_(6a)-C₇ or C₆-C_(6a), R₇ is notpresent. Further, when a double bond is present between C₆-C_(6a),either R₅ or R₆ is not present, and, when present, R₅ is other than ═O.

In other certain embodiments, a double bond is present between C₁-C₂.When a double bond is present between C₁-C₂, R₁ is other than ═O, ═CHCNor ═CHCO₂R_(z), and R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w). In othercertain embodiments, a double bond is present between C₂-C₃. When adouble bond is present between C₂-C₃, R₂ is other than ═O, ═CHCN or═CHCO₂R_(w), and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t). In oneembodiment, when a double bond is present between C₂-C₃, R₃ is CN.

It is to be noted that the present disclosure contemplates and isintended to encompass all of the various combinations and permutations(i.e., combinations of substituent options, locations and stereochemicalconfigurations) possible here.

For example, in various embodiments, compounds of the present disclosurehave the formula of (I-a):

wherein:

R₃ is ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, —CN, β-OH, β-OR_(s), where R_(s) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; and,

- - - denotes an optional C—C bond, resulting in a C═C bond betweenC₂-C₃ with the proviso that when present, R₃ is other than ═O, ═CHCN or═CHCO₂R_(t).

As generally defined above in Formula (I-a), R₃ is ═O, ═CHCN,═CHCO₂R_(t), where R_(t) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, —CN, β-OH, β-OR_(s), where R_(s) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, 13-NO₂, spiroepoxy, or C(O)R_(r), where R_(r)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl. In certainembodiments, R₃ is ═O. In other certain embodiments, R₃ is spiroepoxy.In other certain embodiments, R₃ is β-CN.

As generally defined above in Formula (I-a), - - - denotes an optionalC—C bond, resulting in a C═C bond between C₂-C₃. In one embodiment adouble bond is present between C₂-C₃. When a double bond is presentbetween C₂-C₃ in Formula (I-a), R₃ is —CN.

Accordingly, as noted, the cyclopent[a]anthracenes of Formulas (I) and(I-a) may encompass a number of various structures in accordance withthe present disclosure, including all of the various combinations andpermutations (i.e., combinations of substituent options, locations andstereochemical configurations) possible here.

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts thereof.

In this regard it is to be noted that the structures provided above areof various exemplary embodiments. As such, they should not be viewed ina limiting sense.

1B. CYCLOPENT[A]ANTHRACENE STRUCTURE

Generally speaking, in another embodiment, the cyclopent[a]anthracene ofthe present disclosure has a tetracyclic, fused ring structure (anembodiment of which is illustrated and discussed in greater detailbelow), wherein the C₈-position of the A ring has a hydroxyl or an estersubstituent in the beta configuration, the C₃ position has a substituentattached thereto selected from the group consisting of H, ═O, ═CHCN,═CHCO₂R_(t), where R_(t) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, —CN, α-OH, α-OR_(s), where R_(s) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, and C(O)R_(r), where R_(r)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; and the C₂ positionhas a substituent attached thereto selected from the group consisting ofH, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w) is optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, or optionally substitutedC₂-C₄ alkynyl, α-CN, α-OH, α-OR_(v), where R_(v) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, and C(O)R_(u),where R_(u) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl.

More particularly, however, the present disclosure is directed, incertain embodiments, to a cyclopent[a]anthracene having the structure ofFormula (II):

or a pharmaceutically acceptable salt thereof;wherein:

R₁ is H, ═O, ═CHCN, ═CHCO₂R_(z), where R_(z) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-CN, α-OH, α-OR_(y), where R_(y) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(x), where R_(x) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-CN, α-OH, αOR_(v), where R_(v) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(u), where R_(u) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, —CN, α-OH, α-OR_(s), where R_(s) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₄ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₅ is H, ═O, NH(CH₃)₂, NH(CH₂CH₃)₂, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q),where R_(q) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, CH₂OR_(p), where R_(p) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)R_(o), where R_(o) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)NHR_(n), where R_(n) is optionallysubstituted C C₄ alkyl, optionally substituted C₂-C₄ alkenyl, optionallysubstituted C₂-C₄ alkynyl, or optionally substituted aryl, CH₂NHR_(m),where R_(m) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, or OR_(l), where R_(l) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl;

R₆ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₇ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₉ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl;

R₁₀ is H, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(j), where R_(j) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂OR_(i), where R_(i) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)R_(h), where R_(h) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)NHR_(g), where R_(g) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, or CH₂NHR_(f), where R_(f) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl;

R₁₁ is H or C(O)R_(e), where R_(e) is optionally substituted C₁-C₂₀alkyl, optionally substituted C₂-C₂₀ alkenyl, or optionally substitutedC₂-C₂₀ alkynyl;

R₁₂ is H, optionally substituted morpholinyl, or OR_(k), where R_(k) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl; and,

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between, C₁-C₂, C₂-C₃, C₆-C_(6e), C_(6e)-C₇, or C₉-C₁₀, withthe provisos that when present between: (i) C_(6e)-C₇, R₇ is notpresent; (ii) C₆-C_(6a), R₇ is not present and either R₅ or R₆ is notpresent, and, when present, R₅ is other than ═O; (iii) C₁-C₂, R₁ isother than ═O, ═CHCN or ═CHCO₂R_(z), and R₂ is other than ═O, ═CHCN or═CHCO₂R_(w); and, (iv) C₂-C₃, R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w),and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t).

As generally defined above, R₁ is H, ═O, ═CHCN, ═CHCO₂R_(z), where R_(z)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-CN, α-OH, α-OR_(y),where R_(y) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl,α-NO₂, spiroepoxy, or C(O)R_(x), where R_(x) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl. In a preferred embodiment, R₁ is H.

As generally defined above, R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-CN, α-OH, α-OR_(v),where R_(v) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl,α-NO₂, spiroepoxy, or C(O)R_(u), where R_(u) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl. In a preferred embodiment, R₂ is H. Inanother preferred embodiment, R₂ is ═O.

As generally defined above, R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, —CN, α-OH, α-OR_(e),where R_(s) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl,α-NO₂, spiroepoxy, or C(O)R_(r), where R_(r) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl. In certain embodiments, R₃ is ═O. In othercertain embodiments, R₃ is spiroepoxy. In yet other certain embodiments,R₃ is α-CN. In other certain embodiments, R₃ is H. In one embodiment, adouble bond is present between C₂-C₃ and R₃ is CN.

As generally defined above, R₄ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₄ is methyl. R₄ is in the alphaconfiguration.

As generally defined above, R₅ is H, ═O, NH(CH₃)₂, NH(CH₂CH₃)₂,CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q), where R_(q) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,CH₂OR_(p), where R_(p) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)R_(o), where R_(o) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)NHR_(n), where R_(n) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, CH₂NHR_(m), where R_(m) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, or OR_(l), where R_(l) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In certain embodiments, theoptionally substituted aryl is optionally substituted phenyl ornaphthyl. In a preferred embodiment, R₅ is H.

As generally defined above, R₆ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₆ is H.

As generally defined above, R₇ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₇ is H. In certain embodiments, R₇is in the beta configuration.

As generally defined above, R₉ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In other certain embodiments,the optionally substituted alkyl is optionally substituted alkyl aryl,such as alkyl benzyl. In a preferred embodiment, R₉ is H. R₉ is in thealpha configuration.

As generally defined above, R₁₀ is H, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂,CO₂R_(j), where R_(j) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, CH₂OR_(i), where R_(i) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl,C(O)R_(h), where R_(h) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, oroptionally substituted aryl, C(O)NHR_(g), where R_(g) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, or optionally substituted aryl, orCH₂NHR_(f), where R_(f) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In other certain embodiments,the optionally substituted aryl is optionally substituted phenyl ornaphthyl. In a preferred embodiment, R₁₀ is H. R₁₀ is in the alphaconfiguration.

As generally defined above, R₁₁ is H or C(O)R_(e), where R_(e) isoptionally substituted C₁-C₂₀ alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀ alkynyl. In one embodiment,R_(e) is optionally substituted C₁-C₁₅ alkyl, preferably optionallysubstituted C₁-C₁₀ alkyl, more preferably optionally substituted C₁-C₄alkyl. In another embodiment, R_(e) is optionally substituted C₁-C₁₅alkenyl, preferably optionally substituted C₁-C₁₀ alkenyl, morepreferably optionally substituted C₁-C₄ alkenyl. In yet anotherembodiment, R_(e) is optionally substituted C₁-C₁₅ alkynyl, preferablyoptionally substituted C₁-C₁₀ alkynyl, more preferably optionallysubstituted C₁-C₄ alkynyl. In a preferred embodiment, R₁₁ is H.

As generally defined above, R₁₂ is H, optionally substitutedmorpholinyl, or OR_(k), where R_(k) is optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, optionally substitutedC₂-C₄ alkynyl, or optionally substituted aryl. In certain embodiments,the optionally substituted aryl is optionally substituted phenyl ornaphthyl. In a preferred embodiment, R₁₂ is H. R₁₂ is in the alphaconfiguration.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in either a C═C bond between, C₁-C₂, C₂-C₃, C₆-C_(6a),C_(6a)-C₇, or C₉-C₁₀, with the provisos that when present between: (i)C_(6a)-C₇, R₇ is not present; (ii) C₆-C_(6a), R₇ is not present andeither R₅ or R₆ is not present, and, when present, R₅ is other than ═O;(iii) C₁-C₂, R₁ is other than ═O, ═CHCN or ═CHCO₂R_(z), and R₂ is otherthan ═O, ═CHCN or ═CHCO₂R_(w); and, (iv) C₂-C₃, R₂ is other than ═O,═CHCN or ═CHCO₂R_(w), and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t).

In one embodiment, a double bond is present between C₉-C₁₀. In anotherembodiment, a double bond is present between C_(6a)-C₇. In yet anotherembodiment, a double bond is present between C₆-C_(6a). When a doublebond is present between either C_(6a)-C₇ or C₆-C_(6a), R₇ is notpresent. Further, when a double bond is present between C₆-C_(6a),either R₅ or R₆ is not present, and, when present, R₅ is other than ═O.

In other certain embodiments, a double bond is present between C₁-C₂.When a double bond is present between C₁-C₂, R₁ is other than ═O, ═CHCNor ═CHCO₂R_(z), and R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w). In othercertain embodiments, a double bond is present between C₂-C₃. When adouble bond is present between C₂-C₃, R₂ is other than ═O, ═CHCN or═CHCO₂R_(w), and R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t). In oneembodiment, a double bond is present between C₂-C₃ and R₃ is —CN.

It is to be noted that the present disclosure contemplates and isintended to encompass all of the various combinations and permutations(i.e., combinations of substituent options, locations and stereochemicalconfigurations) possible here.

For example, in various embodiments, compounds of the present disclosurehave the formula of (II-a):

wherein:

R₂ is H, ═O, ═CHCN, ═CHCO₂R_(w), where R_(w) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-CN, α-OH, α-OR_(v), where R_(v) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(u), where R_(u) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; and,

R₃ is H, ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, —CN, α-OH, α-OR_(s), where R_(s) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; and,

- - - denotes an optional C—C bond, resulting in a C═C bond betweenC₂-C₃ with the proviso that when present, R₂ is other than ═O, ═CHCN, or═CHCO₂R_(w) and, R₃ is other than ═O, ═CHCN or ═CHCO₂R_(t).

As generally defined above in Formula (II-a), R₂ is H, ═O, ═CHCN,═CHCO₂R_(w), where R_(w) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, α-CN, α-OH, α-OR_(v), where R_(v) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, or C(O)R_(u), where R_(u)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl. In a preferredembodiment, R₂ is H. In another preferred embodiment, R₂ is ═O.

As generally defined above in Formula (II-a), R₃ is H, ═O, ═CHCN,═CHCO₂R_(t), where R_(t) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, —CN, α-OH, α-OR_(s), where R_(s) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, α-NO₂, spiroepoxy, or C(O)R_(r), where R_(r)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl. In certainembodiments, R₃ is ═O. In other certain embodiments, R₃ is spiroepoxy.In yet other certain embodiments, R₃ is α-CN. In other certainembodiments, R₃ is H.

As generally defined above in Formula (II-a), - - - denotes an optionalC—C bond, resulting in a C═C bond between C₂-C₃. In one embodiment adouble bond is present between C₂-C₃. When a double bond is presentbetween C₂-C₃ in Formula (II-a), R₃ is —CN.

Accordingly, as noted, the cyclopent[a]anthracenes of Formulas (II) and(II-a) may encompass a number of various structures in accordance withthe present disclosure, including all of the various combinations andpermutations (i.e., combinations of substituent options, locations andstereochemical configurations) possible here.

Exemplary compounds of Formula (II) include, but are not limited to:

and pharmaceutically acceptable salts thereof.

In this regard it is to be noted that the structures provided above areof various exemplary embodiments. As such, they should not be viewed ina limiting sense.

2. METHODS OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS

It is to be noted that the compounds or cyclopent[a]anthracenes of thepresent disclosure, may in various embodiments be prepared or used inaccordance with means generally known in the art. For example, incertain embodiments, the cyclopent[a]anthracenes of the presentdisclosure may be prepared or used in a pharmaceutically acceptable saltform. Suitable salt forms include, for example, citrate or chloride saltforms.

In various embodiments of the present disclosure, a pharmaceuticalcomposition is disclosed that may comprise a cyclopent[a]anthracene or acombination of two or more thereof in accordance with the formulas ofthe present disclosure. The compounds or cyclopent[a]anthracenes of thepresent disclosure, as well as the various salt forms and otherpharmaceutically acceptable forms, e.g., solvates and/or hydrates ofcompounds described herein, and pharmaceutical compositions containingthem, may in general be prepared using methods and techniques known inthe art, and/or as described in the Examples provided herein.

Without wishing to be bound by any particular theory, the compounds orcyclopent[a]anthracenes of the present disclosure are useful forpotentiating GABA at GABA_(A) receptors thereby inducing anesthesia ortreating disorders related to GABA function (e.g., insomnia, mooddisorders, Fragile X syndrome, convulsive disorders, anxiety disorders,or symptoms of ethanol withdrawal) in a subject, e.g., a human subject,and are preferably administered in the form of a pharmaceuticalcomposition comprising an effective amount of a compound of the instantdisclosure and optionally a pharmaceutically or pharmacologicallyacceptable carrier.

In one aspect, provided is a method of inducing anesthesia in a subjectin need thereof, the method comprising administering to the subject atherapeutically effective amount of one or more of the above-notedcyclopent[a]anthracenes or pharmaceutically acceptable salts thereof, ora pharmaceutical composition thereof.

In another aspect, provided is a method of treating disorders related toGABA function in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of oneor more of the above-noted cyclopent[a]anthracenes or pharmaceuticallyacceptable salts thereof, or a pharmaceutical composition thereof. Incertain embodiments, the disorder is selected from the group consistingof insomnia, mood disorders, convulsive disorders, Fragile X syndrome,anxiety, or symptoms of ethanol withdrawal.

In one embodiment of the present disclosure, a therapeutically effectiveamount of compound is from about 5 mg/kg to about 20 mg/kg, about 5mg/kg to about 18 mg/kg, about 5 mg/kg to about 16 mg/kg, about 5 mg/kgto about 14 mg/kg, about 5 mg/kg to about 12 mg/kg, about 5 mg/kg toabout 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6 mg/kg to about9 mg/kg, about 7 mg/kg to about 9 mg/kg, or about 8 mg/kg to about 16mg/kg. In certain embodiments, a therapeutically effective amount of thecompound is about 8 mg/kg. It will be appreciated that dose ranges asdescribed herein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, identity of the particularcompound(s), mode of administration, and the like. The desired dosagecan be delivered three times a day, two times a day, once a day, everyother day, every third day, every week, every two weeks, every threeweeks, or every four weeks. In certain embodiments, the desired dosagecan be delivered using multiple administrations (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or more administrations). In other certain embodiments, the compound maybe administered via continuous intravenous (IV) infusion, such as usedby those commonly skilled in the art of general anesthesia.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. It will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually. Exemplarytherapeutically active agents include small organic molecules such asdrug compounds (e.g., compounds approved by the US Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins and cells.

The pharmaceutical composition may also be in combination with at leastone pharmacologically acceptable carrier. The carrier, also known in theart as an excipient, vehicle, auxiliary, adjuvant, or diluent, is anysubstance that is pharmaceutically inert, confers a suitable consistencyor form to the composition, and does not diminish the therapeuticefficacy of the compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic, or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the compounds orcyclopent[a]anthracenes of the present disclosure may be formulated inany conventional manner. Proper formulation is dependent upon the routeof administration chosen. The compositions of the disclosure can beformulated for any route of administration, so long as the target tissueis available via that route. Suitable routes of administration include,but are not limited to, oral, parenteral (e.g., intravenous,intraarterial, subcutaneous, rectal, subcutaneous, intramuscular,intraorbital, intracapsular, intraspinal, intraperitoneal, orintrasternal), topical (nasal, transdermal, intraocular), intravesical,intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal,transurethral, intradermal, aural, intramammary, buccal, orthotopic,intratracheal, intralesional, percutaneous, endoscopical, transmucosal,sublingual, and intestinal administration. In certain embodiments, theroute of administration is oral. In certain embodiments, the route ofadministration is parenteral. In certain embodiments, the route ofadministration is intravenous.

Pharmaceutically acceptable carriers for use in the compositions of thepresent disclosure are well known to those of ordinary skill in the artand are selected based upon a number of factors, including for example:the particular compound used, and its concentration, stability andintended bioavailability; the disease, disorder or condition beingtreated with the composition; the subject, its age, size and generalcondition; and/or the route of administration. Suitable carriers may bereadily determined by one of ordinary skill in the art. (See, forexample, J. G. Nairn, in: Remington's Pharmaceutical Science (A.Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517.)

The compositions may be formulated as tablets, dispersible powders,pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions,suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, orany other dosage form that can be administered orally. Techniques andcompositions for making oral dosage forms useful in the presentdisclosure are described in the following exemplary references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and,Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the present disclosure designed for oraladministration comprise an effective amount of a compound of thedisclosure in a pharmaceutically acceptable carrier. Suitable carriersfor solid dosage forms include sugars, starches, and other conventionalsubstances including lactose, talc, sucrose, gelatin,carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate,calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, cornstarch, potato starch, sodium saccharin, magnesium carbonate,tragacanth, microcrystalline cellulose, colloidal silicon dioxide,croscarmellose sodium, talc, magnesium stearate, and stearic acid.Further, such solid dosage forms may be uncoated or may be coated byknown techniques (e.g., to delay disintegration and absorption).

The compounds and cyclopent[a]anthracenes of the present disclosure mayalso be formulated for parenteral administration (e.g., formulated forinjection via intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes). The compositions of thepresent disclosure for parenteral administration comprise an effectiveamount of the compound in a pharmaceutically acceptable carrier. Dosageforms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions or any other dosage form that can beadministered parenterally. Techniques and compositions for makingparenteral dosage forms are known in the art. Typically formulations forparenteral administration are sterile or are sterilized beforeadministration.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide, 2-pyrrolidinone,1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g.,1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such asmonoacetin, diacetin, and triacetin, aliphatic or aromatic esters suchas ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzylacetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di,or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate,ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters ofsorbitan, fatty acid derived PEG esters, glyceryl monostearate,glyceride esters such as mono, di, or tri-glycerides, fatty acid esterssuch as isopropyl myristrate, fatty acid derived PEG esters such asPEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone,pluronic 60, polyoxyethylene sorbitol oleic polyesters such aspoly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀monooleate, poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono-ricinoleate, polyoxyethylene sorbitan esters(such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, Del.), polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters (such as polyoxyl 40 hydrogenated castor oil,cyclodextrins or modified cyclodextrins (e.g.,beta-hydroxypropyl-cyclodextrin)), saccharide fatty acid esters (i.e.,the condensation product of a monosaccharide (e.g., pentoses, such asribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses suchas glucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfone, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzine; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in the disclosure arewell known to those of ordinary skill in the art, and are identified inThe Handbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa.,1995), The United States Pharmacopeia 24, The National Formulary 19,(National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al.,and Use of Nonaqueous Solvents in Parenteral Products, J. of Pharm.Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include cyclodextrins or modified cyclodextrins(e.g., beta-hydroxypropyl-cyclodextrin) as well as oils rich intriglycerides, for example, safflower oil, soybean oil or mixturesthereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40hydrogenated castor oil. Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®.

Additional minor components can be included in the compositions of thedisclosure for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the compound at the site of administration,protect the stability of the composition, control the pH, facilitateprocessing of the compound into pharmaceutical formulations, and thelike. Preferably, each of these components is individually present inless than about 15 wt % of the total composition, more preferably lessthan about 5 wt %, and most preferably less than about 0.5 wt % of thetotal composition. Some components, such as fillers or diluents, canconstitute up to 90 wt % of the total composition, as is well known inthe formulation art. Such additives include cryoprotective agents forpreventing reprecipitation, surface active, wetting or emulsifyingagents (e.g., lecithin, polysorbate-80, Tween® 80, Pluronic 60,polyoxyethylene stearate), preservatives (e.g.,ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol,phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben),agents for adjusting pH or buffering agents (e.g., acids, bases, sodiumacetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g.,glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetylalcohol, stearyl alcohol, guar gum, methyl cellulose,hydroxypropylcellulose, tristearin, cetyl wax esters, polyethyleneglycol), colorants, dyes, flow aids, non-volatile silicones (e.g.,cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents,flavorings, sweeteners, adsorbents, fillers (e.g., sugars such aslactose, sucrose, mannitol, or sorbitol, cellulose, or calciumphosphate), diluents (e.g., water, saline, electrolyte solutions),binders (e.g., starches such as maize starch, wheat starch, rice starch,or potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropyl methylcellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents(e.g., starches such as maize starch, wheat starch, rice starch, potatostarch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone,agar, alginic acid or a salt thereof such as sodium alginate,croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc,stearic acid or salts thereof such as magnesium stearate, orpolyethylene glycol), coating agents (e.g., concentrated sugar solutionsincluding gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, or titanium dioxide), and antioxidants (e.g.,sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose,phenols, and thiophenols).

Dosage from administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Those with ordinary skill in administering anesthetics can readilydetermine dosage and regimens for the administration of thepharmaceutical compositions of the disclosure or titrating to aneffective dosage for use in treating insomnia, mood disorders,convulsive disorders, anxiety or symptoms of ethanol withdrawal. It isunderstood that the dosage of the compounds will be dependent upon theage, sex, health, and weight of the recipient, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired. For any mode of administration, the actual amount of compounddelivered, as well as the dosing schedule necessary to achieve theadvantageous effects described herein, will also depend, in part, onsuch factors as the bioavailability of the compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present disclosureshould be sufficient to affect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the compound, whether administered orally or by another route, is anyamount that would result in a desired therapeutic response whenadministered by that route. The dosage may vary depending on the dosingschedule, which can be adjusted as necessary to achieve the desiredtherapeutic effect. The most preferred dosage will be tailored to theindividual subject, as is understood and determinable by one of ordinaryskill in the art without undue experimentation.

In one embodiment, solutions for oral administration are prepared bydissolving the compound in any pharmaceutically acceptable solventcapable of dissolving a compound (e.g., ethanol or methylene chloride)to form a solution. An appropriate volume of a carrier which is asolution, such as beta-hydroxypropyl-cyclodextrin, is added to thesolution while stirring to form a pharmaceutically acceptable solutionfor oral administration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving a compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. The solvent can optionally be capable ofevaporating when the solution is dried under vacuum. An additionalcarrier can be added to the solution prior to drying, such asbeta-hydroxypropyl-cyclodextrin. The resulting solution is dried undervacuum to form a glass. The glass is then mixed with a binder to form apowder. The powder can be mixed with fillers or other conventionaltabletting agents and processed to form a tablet for oral administrationto a patient. The powder can also be added to any liquid carrier asdescribed above to form a solution, emulsion, suspension or the like fororal administration.

Emulsions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas Liposyn® II or Liposyn® III emulsions, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient.

Solutions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas beta-hydroxypropyl-cyclodextrin, is added to the solution whilestirring to form a pharmaceutically acceptable solution for parenteraladministration to a patient.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable concentration prior to use as is known in the art.

Still further encompassed by the disclosure are kits (e.g.,pharmaceutical packs). The kits provided may comprise a compound asdescribed herein and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical carrier for dilution or suspensionof the pharmaceutical composition or compound. In some embodiments, thepharmaceutical composition or compound provided in the container and thesecond container are combined to form one unit dosage form.

Optionally, instructions for use are additionally provided in such kitsof the disclosure. Such instructions may provide, generally, forexample, instructions for dosage and administration. In otherembodiments, instructions may further provide additional detail relatingto specialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination with anadditional therapeutic agent.

3. DEFINITIONS

The term “steroid” as used herein describes an organic compoundcontaining in its chemical nucleus the cyclopent[a]anthracene ringsystem.

As used herein, the terms “alpha” (α) and “beta” (β) are used todescribe the absolute configuration and orientation of the structure soas to define the plane and which way up the molecule is represented. Theterm “alpha” refers to substituents below the plane and is shown by abroken line. The term “beta” refers to substituents above the plane andis shown by a solid, bolded line.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this disclosure include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate,laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, mammals, e.g., humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of thedisclosure, the subject is a human.

As used herein, a “therapeutically effective amount” “an amountsufficient” or “sufficient amount” of a compound means the level, amountor concentration of the compound required for a desired biologicalresponse, e.g., analgesia.

The term “saturated” as used herein describes the state in which allavailable valence bonds of an atom (especially carbon) are attached toother atoms.

The term “unsaturated” as used herein describes the state in which notall available valence bonds along the alkyl chain are satisfied; in suchcompounds the extra bonds usually form double or triple bonds (chieflywith carbon).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₄ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₁₋₃, C₁₋₂, C₂₋₄, C₂₋₃ and C₃₋₄ alkyl, while“C₁₋₂₂ alkyl” is intended to encompass, for example, C₁, C₂, C₃, C₄,etc., as well as C₁₋₂₁, C₁₋₂₀, C₁₋₁₅, C₁₋₁₀, C₂₋₂₀, C₂₋₁₅, C₂₋₁₀, C₃₋₁₅,C₃₋₁₀, etc. alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group having from, in some embodiments, 1to 4 carbon atoms (“C₁₋₄ alkyl”), and in other embodiments 1 to 22carbon atoms (“C₁₋₂₂ alkyl”). In some embodiments, an alkyl group has 1to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl grouphas 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkylgroup has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkylgroup has 2 to 4 carbon atom (“C₂₋₄ alkyl”). In yet other embodiments,an alkyl group has 1 to 21 carbon atoms (“C₁₋₂₁ alkyl”), 1 to 20 carbonatoms (“C₁₋₂₀ alkyl”), 1 to 15 carbon atoms (“C₁₋₁₅ alkyl”), 1 to 10carbon atoms (“C₁₋₁₀ alkyl”), etc. Examples of such alkyl groups includemethyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), pentyl (C₅), and thelike.

As used herein, “alkenyl” or “alkene” refers to a radical of astraight-chain or branched hydrocarbon group having from, in someembodiments, 2 to 4 carbon atoms (“C₂₋₄ alkenyl”), and in otherembodiments 2 to 22 carbon atoms (“C₂₋₂₂ alkenyl”), and one or morecarbon-carbon double bonds. In some embodiments, an alkenyl group has 2to 3 carbon atoms (“C₂₋₃ alkenyl”). In some embodiments, an alkenylgroup has 2 carbon atoms (“C₂ alkenyl”). In yet other embodiments, analkenyl group has 2 to 21 carbon atoms (“C₂₋₂₁ alkenyl”), 2 to 20 carbonatoms (“C₂₋₂₀ alkenyl”), 2 to 15 carbon atoms (“C₂₋₁₅ alkenyl”), 2 to 10carbon atoms (“C₂₋₁₀ alkyl”), etc. The one or more carbon-carbon doublebonds can be internal (such as in 2-butenyl) or terminal (such as in1-butenyl). Examples of such alkenyl groups include ethenyl (C₂),1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄), 1-pentenyl (C₅), 2-pentenyl (C₅), and the like.

As used herein, “alkynyl” or “alkyne” refers to a radical of astraight-chain or branched hydrocarbon group having from 2 to 4 carbonatoms and one or more carbon-carbon triple bonds (“C₂₋₁₀ alkynyl”). Insome embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl).

As used herein, “alkoxy” refers to an alkyl, alkenyl, or alkynyl group,as defined herein, attached to an oxygen radical.

Alkyl, alkenyl, alkynyl, and aryl groups, as defined herein, aresubstituted or unsubstituted, also referred to herein as “optionallysubstituted”. In general, the term “substituted”, whether preceded bythe term “optionally” or not, means that at least one hydrogen presenton a group (e.g., a carbon or nitrogen atom) is replaced with apermissible substituent, e.g., a substituent which upon substitutionresults in a stable compound, e.g., a compound which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that result in theformation of a stable compound. The present disclosure contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this disclosure, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary substituents include groups that contain a heteroatom (such asnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogenatom), halogen (e.g., chlorine, bromine, fluorine, or iodine), aheterocycle, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

EXAMPLES

The following Examples describe or illustrate various embodiments of thepresent disclosure. Other embodiments within the scope of the appendedclaims will be apparent to a skilled artisan considering thespecification or practice of the disclosure as described herein. It isintended that the specification, together with the Examples, beconsidered exemplary only, with the scope and spirit of the disclosurebeing indicated by the claims, which follow the Example.

Compound Chemistry

In accordance with the following methods and Examples, the followingcompounds were prepared using methods known in the industry.

In accordance with Scheme 1, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(3S,3aS,5aR,9aR,9bS)-3-(1,1-Dimethylethoxy)dodecahydro-3a-methyl-7H-Benz[e]inden-7-one(1)

Compound 1 was prepared as described previously (see Han, et al.,“Neurosteroid Analogs. 3. The Synthesis and ElectrophysiologicalEvaluation of Benz[e]indene Congeners of Neuroactive Steroids Having the55-Configuration,” J. of Med. Chem., Vol. 38(22), pages 4548-56 (1995)).

(3S,3aS,5aR,9aR,9bS)-2,3,3a,4,5,5a,6,9,9a,9b-Decahydro-3-(1,1-dimethylethoxy)-7-hydroxy-3a-methyl-1H-cyclopenta[a]naphthalene-8-carboxylicacid methyl ester (2)

Dimethyl carbonate (2.7 g, 30 mmol) was added to a suspension of sodiumhydride (1.8 g, 60% in mineral oil, 45 mmol) in THF (50 mL) at roomtemperature. The mixture was refluxed for 30 min. Compound 1 (4.2 g,15.7 mmol) in THF (20 mL) was added by syringe. The reaction wasrefluxed for 14 h and cooled to room temperature. Acetic acid was slowlyadded to the mixture until pH 4-5 and water (50 mL) was added. Theproduct was extracted into EtOAc (100 mL×3) and the combined extractswere dried. The solution was filtered and solvents were removed underreduced pressure. The residue was purified by flash columnchromatography (silica gel eluted with 5% EtOAc in hexanes) to affordcompound 2 (3.6 g, 68%): [α]D25 −63.6 (c 0.42, CHCl3); 1H NMR (CDCl3) δ12.10 (s, 1H), 3.71 (s, 3H), 3.39 (t, J=8.2 Hz, 1H), 1.11 (s, 9H), 0.72(s, 3H); 13C NMR (CDCl3) δ 172.8, 171.6, 96.9, 80.6, 72.1, 51.3, 49.9,42.9, 38.3, 36.9, 36.6, 36.1, 31.0, 28.7, 28.6, 28.5, 27.7, 23.5, 11.5.Anal. Calcd for (C20H32O4): C, 71.39; H, 9.59. Found: C, 71.50, H, 9.61.

(3S,3aS,5aR,9aR,9bS)-3-(1,1-Dimethylethoxy)dodecahydro-3a-methyl-7-oxo-8-(3-oxo-butyl)-cyclopenta[a]naphthalene-8-carboxylicacid methyl ester (3)

Neutral alumina (6.0 g) was heated at 180° C. under high vacuum for 4 h.After cooling down to room temperature, the flask was charged with N2.Compound 2 (3.6 g, 6.5 mmol), vinyl methyl ketone (910 mg, 13 mmol), andCH₂Cl₂ (25 mL) were added to the anhydrous alumina at room temperature.The mixture was stirred at room temperature for 16 h. The suspension wasfiltered through Celite® 545 and washed with CH₂Cl₂ (50 mL×3). Thesolvent was removed under reduced pressure and the residue was purifiedby flash column chromatography (silica gel eluted with 10% EtOAc inhexanes) to afford diastereomeric 8R/8S product 3 (3.61 g, 95%,major/minor=10/1). The major diastereomer had: [α]D25 −80.7 (c 0.55,CHCl3); 1H NMR (CDCl3) δ 3.63 (s, 3H), 3.32 (t, J=8.2 Hz, 1H), 2.03 (s,3H), 1.03 (s, 9H), 0.71 (s, 3H); 13C NMR (CDCl3) δ 208.4, 207.4, 172.7,80.1, 72.0, 60.7, 51.9, 49.1, 44.9, 43.4, 43.1, 38.6, 38.3, 36.3, 35.1,30.7, 29.8, 29.0, 28.5 (3C), 26.5, 23.2, 11.6. Anal. Calcd for(C24H38O5): C, 70.90; H, 9.42. Found: C, 70.72; H, 9.40.

(3S,3aS,5aR,10aS,11aR,11bS)-1,2,3,3a,4,5,5a,6,9,10,10a,11,11a,11b-Tetradecahydro-3-(1,1-dimethylethoxy)-3a-methyl-8H-Cyclopent[a]anthracen-8-one(4)

Lithium chloride (1.53 g, 36 mmol) was added to compound 3 (3.6 g, 12.0mmol) in anhydrous DMF (40 mL) at room temperature. The reaction wasrefluxed for 16 h and the solvent was removed under reduced pressure toafford the crude three ring decarboxylation product. The crude productwas dissolved in EtOH (15 mL) and 0.5 N NaOH (15 mL) was added at roomtemperature. The reaction was refluxed and monitored by TLC. After 30min, aqueous NH₄Cl was added. The product was extracted into EtOAc (100mL×3) and dried. The solvent was filtered and removed under reducedpressure. The residue was purified by flash column chromatography(silica gel eluted with 10% EtOAc in hexanes) to afford compound 4 (2.1g, 71%, two steps) as a colorless oil: [α]_(D) ²⁵ −6.8 (c 0.44, CHCl₃);¹H NMR (CDCl₃) δ 5.72 (s, 1H), 3.33 (t, J=8.2 Hz, 1H), 1.05 (s, 9H),0.69 (s, 3H); ¹³C NMR (CDCl₃) δ 199.8, 166.5, 124.1, 80.3, 71.9, 49.4,44.2, 42.9, 41.8, 40.2, 38.4, 37.4, 36.6, 36.5, 30.9, 29.0, 28.9, 28.5(3C), 23.2, 11.5.

(3S,3aS,5aR,10aS,11aR,11bS)-1,2,3,3a,4,5,5a,6,9,10,10a,11,11a,11b-Tetradecahydro-3-hydroxy-3a-methyl-8H-Cyclopent[a]anthracen-8-one(5)

To a solution of compound 4 (2.05 g, 6.2 mmol) in MeOH (30 mL) was added3 N HCl (30 mL) at room temperature. The reaction was stirred andrefluxed for 4 h. After cooling to room temperature, the products wereextracted into CH₂Cl₂ (50 mL×3), dried, filtered, and concentrated. Theresidue was purified by flash column chromatography (silica gel elutedwith 20% EtOAc in hexanes) to give compound 5 (1.15 mg, 68%) as a whitesemisolid: [α]_(D) ²⁵ −30.5 (c 0.53, CHCl₃); ¹H NMR (CDCl₃) δ 5.75 (s,1H), 3.63 (t, J=8.2 Hz, 1H), 0.75 (s, 3H); ¹³C NMR (CDCl₃) δ 200.2,166.8, 124.1, 81.3, 49.2, 44.1, 43.4, 41.8, 40.3, 38.4, 37.4, 36.5,36.2, 30.0, 29.0, 28.9, 22.9, 11.1; IR ν_(max) 3420, 1659 cm⁻¹. Anal.Calcd for (C₁₈H₂₆O₂): C, 78.79; H, 9.55. Found: C, 78.61; H, 9.46.

(3aS,5aR,6aR,10aS,11aR,11bS)-Tetradecahydro-3a-methylcyclopent[a]anthracene-3,8(2H,4H)-dione (6)

A three-neck flask fitted with a dry ice condenser was cooled to −78°C., and anhydrous ammonia (100 mL) was condensed into the flask. Lithium(245 mg, 35 mmol) was added, and the resulting blue solution was stirredfor 0.5 h. To this was added a solution of compound 5 (950 mg, 3.46mmol) in dry THF (30 mL). After 3 h, solid NH₄Cl was added until theblue color disappeared and the flask was allowed to warm to roomtemperature overnight. Aqueous NH₄Cl was added and the product wasextracted into EtOAc (100 mL×3). The combined extracts were washed withbrine, dried and the solvent evaporated. The residue was dissolved inacetone (40 mL) and Jones reagent was added at 0° C. until abrown-yellowish color persisted. After 10 min, excess oxidant wasconsumed with by adding 2-propanol (1.0 mL). Brine (50 mL) was added andthe product extracted into EtOAc (50 mL×3). The combined extracts weredried, filtered, and concentrated. The residue was purified by flashcolumn chromatography (silica gel eluted with 20% EtOAc in hexanes) togive compound 6 (741 mg, 71%, 2 steps) as a white solid: mp 110-112° C.,[α]_(D) ²⁵ +43.5 (c 0.37, CHCl₃); ¹H NMR (CDCl₃) δ 0.83 (s, 3H); ¹³C NMR(CDCl₃) δ 220.7, 211.1, 50.1, 48.2, 48.1, 43.1, 43.0, 41.3, 41.1, 40.3,40.2, 35.8, 35.6, 33.0, 31.3, 28.3, 21.3, 13.7; IR ν_(max) 1737, 1714cm⁻¹. Anal. Calcd for (C₁₈H₂₆O₂): C, 78.79; H, 9.55. Found: C, 78.57; H,9.40.

In accordance with Scheme 2, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(3aS,5aR,6aR,8S,10aS,11aR,11bS)-Hexadecahydro-8-hydroxy-3a-methyl-cyclopent[a]anthracen-3-one(7)

To a solution of compound 6 (450 mg, 1.6 mmol) in THF (15 mL) was addedK-selectride (2.0 mmol, 2.0 mL, 1.0 M in THF) at 78° C. After 3 h, 10%aqueous NaOH (15 mL) and 30% H₂O₂ (4 mL) were added at 78° C. Afteraddition, the reaction was warmed up to room temperature for 1 h. Theproduct was extracted into EtOAc (50 mL×3) and the combined extractswere dried, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel, 30% EtOAc in hexanes) to givecompound 7 (380 mg, 84%) as a white solid: mp 152-154° C., [α]_(D) ²⁵+72.4 (c 0.39, CHCl₃); ¹H NMR (CDCl₃) δ 4.08-4.06 (m, 1H), 0.85 (s, 3H);¹³C NMR (CDCl₃) δ 221.3, 66.6, 50.3, 48.3, 44.2, 42.6, 40.7, 40.1, 40.0,36.9, 36.2, 35.7, 32.8, 31.5, 28.7, 27.2, 21.5, 13.8; IR ν_(max) 3444,1736 cm⁻¹. Anal. Calcd for (C₁₈H₂₈₀₂): C, 78.21; H, 10.21. Found: C,77.97; H, 10.06.

(2′S,3S,3aS,5aR,6aR,8S,10aS,11aR,11bS)-Hexadecahydro-3a-methyl-spiro[3H-cyclopent[a]anthracene-3,2′-oxiran]-8-ol(8)

To a solution of compound 7 (55 mg, 0.2 mmol) in DMF (3 mL) was addedtrimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide(112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) wasadded and the product extracted into EtOAc (50 mL×3). Solvents weredried, filtered, and concentrated. The residue was purified by flashcolumn chromatography (silica gel eluted with 20% EtOAc in hexanes) toafford compound 8 (40 mg, 70%): mp 140-142° C.; [α]_(D) ²⁰ −10.7 (c0.15, CHCl₃); ¹H NMR (CDCl₃) δ 4.11-4.10 (m, 1H), 2.91 (s, J=5.1 Hz,1H), 2.60 (s, J=5.1 Hz, 1H), 0.88 (s, 3H); ¹³C NMR (CDCl₃) δ 70.6, 66.9,53.7, 51.7, 44.2, 42.8, 41.5, 40.8, 40.3, 40.1, 37.7, 36.3, 33.9, 32.9,29.1, 29.0, 27.3, 23.2, 14.5; IR ν_(max) 3406, 1443 cm⁻¹. Anal. Calcdfor (C₁₉H₃₀O₂): C, 78.57; H, 10.41. Found: C, 78.67; H, 10.24.

In accordance with Scheme 3, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(3aS,5aR,6aR,8S,10aS,11aR,11bS)-Hexadecahydro-8-(methoxymethoxy)-3a-methyl-3H-cyclopent[a]anthracen-3-one(9)

To a solution of compound 8 (200 mg, 0.72 mmol) in dried dichloromethane(20 mL) was added DIPEA (260 mg, 2.0 mmol), chloromethyl methyl ether(121 mg, 1.5 mmol), and DMAP (10 mg) at room temperature. After 16 h,water was added and the product extracted into dichloromethane (100mL×2). The combined extracts were dried, filtered, and removed. Theresidue was purified by flash column chromatography (silica gel elutedwith 10% EtOAc in hexanes) to afford compound 9 (210 mg, 91%): [α]_(D)²⁰ +43.9 (c 0.18, CHCl₃); ¹H NMR (CDCl₃) δ 4.62 (s, 2H), 3.86 (s, br,1H), 3.32 (s, 3H), 2.43 (dd, J=18.8 Hz, 8.6 Hz, 1H), 0.84 (s, 3H); ¹³CNMR (CDCl₃) δ 221.1, 94.5, 71.6, 55.0, 50.3, 48.3, 44.1, 42.5, 40.7,40.2, 37.8, 36.9, 36.7, 35.7, 31.5, 30.3, 28.7, 27.8, 21.4, 13.8; IRν_(max) 1738 cm⁻¹.

1,1,1-Trifluoromethanesulfonic acid(3aS,5aR,6aR,8S,10aS,11aR,11bS)-8-(methoxymethoxy)-3a-methyl-3a,4,5,5a,6,6a,7,8,9,10,10a,11,11a,11btetradecahydro-1H-cyclopent[a]anthracen-3-yl ester (10)

To a solution of compound 9 (200 mg, 0.6 mmol) in THF (15 mL) was addedpotassium bis(trimethylsilyl) amide (0.5 M in toluene, 2.0 mL, 1.0 mmol)at −78° C. After 30 min, N-phenyltrifluoromethanesulfonimide (378 mg,1.0 mmol) in 5 mL of THF was added at −78° C. After 2 h at 78° C., waterwas added and the product extracted into EtOAc (50 mL×3). The combinedextracts were dried, filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel eluted with 10%EtOAc in hexanes) to afford compound 10 (350 mg) which was immediatelyconverted in compound 11.

(3aS,5aR,6aR,8S,10aS,11aR,11bS)-8-(Methoxymethoxy)-3a-methyl-3a,4,5,5a,6,6a,7,8,9,10,10a,11,11a,11b-tetradecahydro-1H-cyclopent[a]anthracene-3-carbonitrile (11)

To compound 10 (350 mg) in a 50 mL flask was added sodium cyanide (150mg, 3.0 mmol), copper (I) iodide (60 mg, 0.3 mmol) and Pd(PPh₃)₄ (30 mg)at room temperature. Acetonitrile (15 mL) was added and the reaction wasrefluxed for 1 h. Aqueous NH₄Cl was added and the product extracted intoEtOAc (50 mL×3). The combined extracts were dried, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel eluted with 10% EtOAc in hexanes) to afford compound 11 (203mg containing an impurity from the sulfonimide reagent): ¹H NMR (CDCl₃)δ 6.58 (s, 1H), 4.64 (s, 2H), 3.85 (s, br, 1H), 3.34 (s, 3H), 0.85 (s,3H); ¹³C NMR (CDCl₃) δ 148.3, 127.0, 117.6, 94.3, 72.1, 55.1, 54.9,48.8, 44.4, 42.4, 39.9, 39.6, 37.5, 37.5, 36.7, 33.8, 32.5, 30.1, 28.9,27.6, 16.3; IR ν_(max) 3140, 2218 cm⁻¹.

(3aS,5aR,6aR,8S,10aS,11aR,11bS)-8-Hydroxy-3a-methyl-3a,4,5,5a,6,6a,7,8,9,10,10a,11,11a,11b-Tetradecahydro-1H-cyclopent[a]anthracene-3-carbonitrile(12)

Compound 11 (203 mg with the impurity from the suflonimide reagent) inmethanol (10 mL) was added 6 N HCl (15 ml) at room temperature. After 14h, the mixture was extracted into CH₂Cl₂ (50 mL×2). The combinedextracts were dried, filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel eluted with 25%EtOAc in hexanes) to afford compound 12 (106 mg, 62% from compound 9):mp 164-166° C., [α]_(D) ²⁵ −16.0 (c 0.10, CHCl₃); ¹H NMR (CDCl₃) δ 4.11(s, br, 1H), 0.91 (s, 3H); ¹³C NMR (CDCl₃) δ 147.3, 127.6, 115.9, 66.7,55.1, 48.8, 44.6, 42.7, 40.1, 40.0, 39.7, 37.9, 36.3, 33.9, 32.8, 32.5,29.0, 27.2, 16.4; IR ν_(max) 3429, 2209, 1443 cm⁻¹. Anal. Calcd for(C₁₉H₂₇NO): C, 79.95; H, 9.53; N, 4.91. Found: C, 80.00; H, 9.39; N,4.96.

(3S,3aS,5aR,6aR,8S,10aS,11aR,11bS)-Hexadecahydro-8-hydroxy-3a-methyl-cyclopent[a]anthracene-3-carbonitrile(13)

To a solution of compound 12 (60 mg, 0.21 mmol) in EtOAc (40 mL) wasadded Pd/C (50 mg). Hydrogenation was carried out under 7 atm H₂ at roomtemperature for 3 h. The reaction mixture was filtered through Celite®545 which was washed with EtOAc (100 mL). Solvents were removed and theresidue was purified by flash column chromatography (silica gel elutedwith 10% EtOAc in hexanes) to afford compound 13 (45 mg, 75%): 153-155°C.; [α]D²⁵ +28.2 (c 0.17, CHCl₃); ¹H NMR (CDCl₃) δ4.11-4.10 (m, 1H),2.30 (t, J=9.2 Hz, 1H), 0.92 (s, 3H); ¹³C NMR (CDCl₃) δ 121.4, 66.8,66.7, 53.2, 45.0, 43.8, 42.7, 41.6, 40.3, 40.0, 38.1, 37.1, 36.2, 32.9,29.1, 27.2, 26.5, 24.2, 14.5; IR ν_(max) 3434, 2237, 1448 cm⁻¹. Anal.Calcd for (C₁₉H₂₉NO): C, 79.39; H, 10.17; N, 4.87. Found: C, 79.37; H,10.16; N, 4.79.

In accordance with Scheme 4, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(3R,3aR,5aS,9aS,9bR)-3-(1,1-Dimethylethoxy)dodecahydro-3a-methyl-7H-Benz[e]inden-7-one(14)

Compound 14 was prepared as described previously (see Hu et al.,“Neurosteroid analogs. Part 5. Enantiomers of neuroactive steroids andbenz[e]indenes: total synthesis, electrophysiological effects on GABAreceptor function and anesthetic actions in tadpoles,” J. of the Chem.Soc., Perkin Transactions 1: Organic and Bio-Organic Chemistry, Vol. 24,pages 3665-3672 (1997)).

(3R,3aR,5aS,9aS,9bR)-2,3,3a,4,5,5a,6,9,9a,9b-Decahydro-3-(1,1-dimethylethoxy)-7-hydroxy-3a-methyl-1H-cyclopenta[a]naphthalene-8-carboxylis acid methyl ester (15)

Dimethyl carbonate (1.62 g, 18 mmol) was added to a suspension of sodiumhydride (0.72 g, 60% in mineral oil, 18 mmol) in THF (50 mL) at roomtemperature. The mixture was refluxed for 30 min. Then compound 14 (2.4g, 9 mmol) in THF (20 mL) was added by syringe. The reaction wasrefluxed for 14 h and cooled down to room temperature. Acetic acid wasslowly added to the mixture until pH 4-5 and water (50 mL) was added.The products were extracted into EtOAc (100 mL×3) and the combinedextracts were dried. The solution was filtered and solvents were removedunder reduced pressure. The residue was purified by flash columnchromatography (silica gel eluted with 5% EtOAc in hexanes) to affordcompound 15 (2.1 g, 72%): ¹H NMR (CDCl₃) δ 12.10 (s, 1H), 3.72 (s, 3H),3.40 (t, J=7.7 Hz, 1H), 1.11 (s, 9H), 0.73 (s, 3H); ¹³C NMR (CDCl₃) δ172.9, 171.6, 96.9, 80.7, 72.1, 51.2, 50.0, 42.9, 38.4, 37.0, 36.7,36.2, 31.1, 28.7 (3C), 27.8, 23.6, 11.5. MS (FAB) for [C₂₀H₃₂O₄+H]⁺:337.2379. Found: 337.2379.

(3R,3aR,5aS,9aS,9bR)-3-(1,1-Dimethylethoxy)dodecahydro-3a-methyl-7-oxo-8-(3-oxo-butyl)-cyclopenta[a]naphthalene-8-carboxylicacid methyl ester (16)

Neutral alumina (4.0 g) was heated at 180° C. under high vacuum for 4 h.After cooling down to room temperature, the flask was filled with N₂.Compound 15 (2.1 g, 6.5 mmol), vinyl methyl ketone (910 mg, 13 mmol),and CH₂Cl₂ (20 mL) were added to the anhydrous alumina at roomtemperature. The mixture was stirred at room temperature for 16 h. Thesuspension was filtered through Celite® 545 which was washed with CH₂Cl₂(50 mL×3). The solvent was removed under reduced pressure and theresidue was purified by flash column chromatography (silica gel elutedwith 10% EtOAc in hexanes) to afford diastereomeric 8R/8S product 16(2.4 g, 95%, major/minor=7.5/1). The major diastereomer had: ¹H NMR(CDCl₃) δ 3.97 (s, 3H), 3.32 (t, J=7.7 Hz, 1H), 2.02 (s, 3H), 1.02 (s,9H), 0.70 (s, 3H); ¹³C NMR (CDCl₃) δ 208.3, 207.2, 172.7, 80.2, 72.0,60.7, 51.9, 49.1, 45.0, 43.4, 43.1, 38.6, 38.3, 36.4, 35.2, 30.7, 29.7,29.0, 28.5 (3C), 26.6, 23.2, 11.6. MS (FAB) for [C₂₄H₃₈O₅+H]⁺: 407.2789.Found: 407.2794.

(3R,3aR,5aS,10aR,11aS,11bR)-1,2,3,3a,4,5,5a,6,9,10,10a,11,11a,11b-Tetradecahydro-3-(1,1-dimethylethoxy)-3a-methyl-8H-Cyclopent[a]anthracen-8-one(17)

Lithium chloride (1.02 g, 24 mmol) was added to compound 16 (2.4 g, 8.0mmol) in anhydrous DMF (30 mL) at room temperature. The reaction wasrefluxed for 16 h and the solvent was removed under reduced pressure toafford the crude decarboxylation product. The crude product wasdissolved in EtOH (15 mL) and 0.5 N NaOH (15 mL) was added at roomtemperature. The reaction was refluxed and monitored by TLC. After 30min, aqueous NH₄Cl was added and the product was extracted into EtOAc(100 mL×3) and dried. The solvent was filtered and removed under reducedpressure. The residue was purified by flash column chromatography(silica gel eluted with 10% EtOAc in hexanes) to afford compound 17 (990mg, 51%) as a colorless oil: ¹H NMR (CDCl₃) δ 5.71 (s, 1H), 3.33 (t,J=7.7 Hz, 1H), 1.04 (s, 9H), 0.68 (s, 3H); ¹³C NMR (CDCl₃) δ 199.6,166.4, 124.1, 80.4, 71.9, 49.3, 44.3, 42.9, 41.8, 40.2, 38.5, 37.4,36.6, 36.4, 30.9, 29.1, 29.0, 28.5 (3C), 23.3, 11.5. MS (FAB) for[C₂₂H₃₄O₂+H]⁺: 331.2637. Found: 331.2637.

(3R,3aR,5aS,10aR,11aS,11bR)-1,2,3,3a,4,5,5a,6,9,10,10a,11,11a,11b-Tetradecahydro-3-hydroxy-3a-methyl-8H-Cyclopent[a]anthracen-8-one(18)

To compound 17 (990 mg, 3.0 mmol) in MeOH (20 mL) was added 3 N HCl (20mL) at room temperature. The reaction was stirred and refluxed for 16 h.After cooling to room temperature, the product was extracted into CH₂Cl₂(50 mL×3), dried, filtered, and concentrated. The residue was purifiedby flash column chromatography (silica gel eluted with 20% EtOAc inhexanes) to give compound 18 (680 mg, 83%) as a white semisolid: ¹H NMR(CDCl₃) δ 5.71 (s, 1H), 3.59 (t, J=8.2 Hz, 1H), 0.70 (s, 3H); ¹³C NMR(CDCl₃) δ 200.1, 166.8, 124.0, 81.1, 49.3, 44.0, 43.3, 41.7, 40.2, 38.3,37.3, 36.3, 36.1, 29.9, 28.9, 28.8, 22.8, 11.0. MS (FAB) for[C₁₈H₂₆O₂+Na]⁺: 297.1830. Found: 297.1826.

(3aR,5aS,6aS,9aR,10aR,11aS,11bR)-Tetradecahydro-3a-methyl-cyclopent[a]anthracene-3,8(2H,4H)-dione(19)

A three-neck flask fitted with a dry ice condenser was cooled to −78° C.and anhydrous ammonia (100 mL) was condensed into the flask. Lithium(0.14 g, 20 mmol) was added and the resulting blue solution was stirredfor 0.5 h. To this was added a solution of compound 18 (650 mg, 2.35mmol) in dry THF (30 mL). After 3 h, solid NH₄Cl was added until theblue color disappeared. The quenched reaction was allowed to warm toroom temperature overnight. Aqueous NH₄Cl was added and the product wasextracted into EtOAc (100 mL×3). The combined organic fractions werewashed with brine, dried and the solvent evaporated. The residue wasdissolved in acetone (40 mL) and Jones reagent was added at 0° C. untila brown-yellowish color persisted. After 10 min, excess oxidant wasconsumed with added 2-propanol (1.0 mL). Then, brine (50 mL) was addedand the product extracted into EtOAc (50 mL×3). The combined extractswere dried, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel eluted with 20% EtOAc inhexanes) to give compound 19 (453 mg, 70%) as a white solid: mp 111-113°C., [α]_(D) ²⁵ −43.1 (c 0.26, CHCl₃); ¹H NMR (CDCl₃) δ 0.82 (s, 3H); ¹³CNMR (CDCl₃) δ 220.4, 210.9, 50.1, 48.1, 48.0, 43.2, 43.0, 41.3, 41.1,40.3, 40.2, 35.8, 35.5, 33.0, 31.3, 28.3, 21.3, 13.7; IR ν_(max) 1737,1713 cm⁻¹.

In accordance with Scheme 5, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(3aR,5aS,6aS,8R,10aR,11aS,11bR)-Hexadecahydro-8-hydroxy-3a-methyl-3H-cyclopent[a]anthracen-3-one(20)

To a solution of compound 19 (240 mg, 0.87 mmol) in THF (10 mL) wasadded K-selectride (1.0 mmol, 1.0 mL, 1.0 M in THF) at 78° C. After 3 h,10% of aqueous NaOH (10 mL) and 30% H₂O₂ (3 mL) were added at 78° C.After addition, the mixture was warmed up to room temperature for 1 h.The product was extracted into EtOAc (50 mL×3) and the combined extractswere dried, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel eluted with 30% EtOAc inhexanes) to give compound 20 (180 mg, 75%) as a white solid: mp 152-154°C., [α]_(D) ²⁵ −72.9 (c 0.21, CHCl₃); ¹H NMR (CDCl₃) δ 4.08-4.06 (m,1H), 0.83 (s, 3H); ¹³C NMR (CDCl₃) δ 221.2, 66.6, 50.4, 48.3, 44.2,42.6, 40.7, 40.1, 40.0, 36.9, 36.2, 35.7, 32.8, 31.5, 28.7, 27.2, 21.4,13.8; IR ν_(max) 3424, 1736 cm⁻¹. Anal. Calcd for (C₁₈H₂₈O₂): C, 78.21;H, 10.21. Found: C, 78.60; H, 9.96.

(2′R,3R,3aR,5aS,6aS,8R,10aR,11aS,11bR)-Hexadecahydro-3a-methyl-spiro[3H-cyclopent[a]anthracene-3,2′-oxiran]-8-ol (21)

To a solution of compound 20 (42 mg, 0.16 mmol) in DMF (3 mL) was addedtrimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide(112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) wasadded and the product extracted into EtOAc (50 mL×3). Solvents weredried, filtered, and concentrated. The residue was purified by flashcolumn chromatography (silica gel eluted with 20% EtOAc in hexanes) toafford compound 21 (31 mg, 71%): mp 143-145° C.; [α]_(D) ²⁰ +10.5 (c0.18, CHCl₃); ¹H NMR (CDCl₃) δ 4.11 (s, br, 1H), 2.91 (s, J=5.1 Hz, 1H),2.60 (s, J=5.1 Hz, 1H), 0.89 (s, 3H); ¹³C NMR (CDCl₃) δ 70.6, 66.9,53.7, 51.7, 44.2, 42.8, 41.5, 40.8, 40.3, 40.1, 37.7, 36.4, 33.9, 32.9,29.1, 29.0, 27.3, 23.2, 14.5; IR ν_(max) 3400, 1443 cm⁻¹. Anal. Calcdfor (C₁₉H₃₀O₂): C, 78.57; H, 10.41. Found: C, 78.34; H, 10.77.

In accordance with Scheme 6, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(3aR,5aS,6aS,8R,10aR,11aS,11bR)-Hexadecahydro-8-(methoxymethoxy)-3a-methyl-3H-cyclopent[a]anthracen-3-one(22)

To a solution of compound 21 (100 mg, 0.36 mmol) in drieddichloromethane (15 mL) was added DIPEA (130 mg, 1.0 mmol), chloromethylmethyl ether (121 mg, 1.5 mmol), and DMAP (10 mg) at room temperature.After 16 h, water was added and the product extracted intodichloromethane (100 mL×2). The combined extracts were dried, filtered,and solvent removed. The residue was purified by flash columnchromatography (silica gel eluted with 10% EtOAc in hexanes) to affordcompound 22 (116 mg, 100%): ¹H NMR (CDCl₃) δ 4.61 (s, 2H), 3.86 (s, br,1H), 3.32 (s, 3H), 2.42 (dd, J=19.2 Hz, 9.6 Hz, 1H), 0.84 (s, 3H); ¹³CNMR (CDCl₃) δ 221.1, 94.5, 71.6, 55.0, 50.3, 48.3, 44.2, 42.5, 40.7,40.2, 37.8, 36.9, 36.7, 35.7, 31.5, 30.3, 28.7, 27.8, 21.5, 13.8; IRν_(max) 1739, 1041 cm⁻¹.

1,1,1-Trifluoromethanesulfonic acid(3aR,5aS,6aS,8R,10aR,11aS,11bR)-8-(methoxymethoxy)-3a-methyl-3a,4,5,5a,6,6a,7,8,9,10,10a,11,11a,11b-tetradecahydro-1H-cyclopent[a]anthracen-3-ylester (23)

To a solution of compound 22 (96 mg, 0.3 mmol) in THF (15 mL) was addedpotassium bis(trimethylsilyl) amide (0.5 M in toluene, 1.0 mL, 0.5 mmol)at 78° C. After 30 min, the N-phenyltrifluoromethanesulfonimide (189 mg,0.5 mmol) in 5 mL of THF was added at 78° C. After 2 h at 78° C., waterwas added and the product extracted into EtOAc (50 mL×3). The combinedextracts were dried, filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel eluted with 10%EtOAc in hexanes) to afford compound 23 (200 mg with an impurity fromthe sulfonamide reagent) which was immediately converted to compound 24.

(3aR,5aS,6aS,8R,10aR,11aS,11bR)-8-(Methoxymethoxy)-3a-methyl-3a,4,5,5a,6,6a,7,8,9,10,10a,11,11a,11b-tetradecahydro-1H-cyclopent[a]anthracene-3-carbonitrile(24)

To compound 23 (185 mg with sulfonimide impurity) in a 50 mL round flaskwas added sodium cyanide (150 mg, 3.0 mmol), copper (I) iodide (60 mg,0.3 mmol) and Pd(PPh₃)₄ (30 mg) at room temperature. Acetonitrile (15mL) was added and the mixture was refluxed for 1 h. Aqueous NH₄Cl wasadded and the product extracted into EtOAc (50 mL×3). The combinedextracts were dried, filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel eluted with 10%EtOAc in hexanes) to afford compound 24 (85 mg, 86% from compound 22):¹H NMR (CDCl₃) δ 6.61 (d, J=1.2 Hz, 1H), 4.65 (s, 2H), 3.90 (s, br, 1H),3.36 (s, 3H), 0.92 (s, 3H); ¹³C NMR (CDCl₃) δ 147.2, 127.7, 115.9, 94.6,71.7, 55.2, 48.8, 44.6, 42.6, 40.2, 39.8, 37.9, 37.8, 36.9, 34.0, 32.5,30.4, 29.0, 27.8, 16.4; IR ν_(max) 3396, 2209 cm⁻¹.

(3aR,5aS,6aS,8R,10aR,11aS,11bR)-8-Hydroxy-3a-methyl-3a,4,5,5a,6,6a,7,8,9,10,10a,11,11a,11b-Tetradecahydro-1H-cyclopent[a]anthracene-3-carbonitrile(25)

To compound 24 (83 mg, 0.25 mmol) in methanol (10 mL) was added 6 N HCl(10 ml) at room temperature. After 14 h, the mixture was extracted intoCH₂Cl₂ (50 mL×2). The combined extracts were dried, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel eluted with 25% EtOAc in hexanes) to afford compound 25 (38mg, 53%): mp 165-167° C., [α]_(D) ²⁵ +16.2 (c 0.13, CHCl₃); ¹H NMR(CDCl₃) δ 4.11 (s, br, 1H), 0.92 (s, 3H); ¹³C NMR (CDCl₃) δ 147.3,127.6, 115.9, 66.7, 55.1, 48.8, 44.6, 42.7, 40.1, 40.0, 39.7, 37.9,36.3, 33.9, 32.8, 32.5, 29.0, 27.7, 16.4; IR ν_(max) 3376, 2213 cm⁻¹.Anal. Calcd for (C₁₉H₂₇NO): C, 79.95; H, 9.53; N, 4.91. Found: C, 80.06;H, 9.49; N, 4.95.

In accordance with Scheme 7, the following compounds were prepared usingmethods generally known in the art and as outlined below.

(2E,3aR,5aS,6aS,8R,10aR,11aS,11bR)-8-Hydroxy-3a-methyl-2-(phenylmethylene)-hexadecahydro-3H-cyclopent[a]anthracen-3-one(26)

To a solution of compound 25 (110 mg, 0.40 mmol) in ethanol (10 mL) wasadded benzaldehyde (86 mg, 0.8 mmol) and KOH (50 mg) at roomtemperature. After 16 h, aqueous NH₄Cl (50 mL) was added and the productwas extracted into EtOAc (50 mL×3). Solvents were dried, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel eluted with 20% EtOAc in hexanes) to give compound 26 (144mg, 100%) as a white solid: ¹H NMR (CDCl₃) δ 7.45-7.21 (m, 6H), 5.12 (s,br, 1H), 4.06 (s, br, 1H), 0.87 (s, 3H); ¹³C NMR (CDCl₃) δ 209.9, 136.0,135.5, 132.9, 130.1 (2C), 129.9, 128.5 (2C), 66.6, 48.3, 48.0, 44.2,42.5, 40.2, 40.1, 39.8, 37.0, 36.0, 32.6, 31.5, 28.9, 28.7, 27.1, 14.4;IR ν_(max) 3356, 1716 cm⁻¹.

(2E,3R,3aR,5aS,6aS,8R,10aR,11aS,11bR)-3a-Methyl-2-(phenylmethylene)-hexadecahydro-cyclopent[a]anthracene-3,8-diol(27)

To a solution of compound 26 (144 mg, 0.36 mmol) in ethanol (20 mL) wasadded CeCl₃.7H₂O (559 mg, 1.5 mmol) and NaBH₄ (57 mg, 1.5 mmol) at 0° C.After 1 h, aqueous NH₄Cl (50 mL) was added and the product was extractedinto EtOAc (50 mL×3). Solvents were dried, filtered, and concentrated.The residue was purified by flash column chromatography (silica geleluted with 30% EtOAc in hexanes) to give compound 27 (145 mg, 100%) asa white solid: ¹H NMR (CDCl₃) δ 7.54-7.09 (m, 5H), 6.44-6.43 (m, 1H),4.08-4.00 (m, 3H), 1.97 (s, 3H), 0.63 (s, 3H); ¹³C NMR (CDCl₃) δ 146.28,138.1, 128.5 (2C), 128.4 (2C), 126.5, 123.1, 85.2, 67.1, 47.6, 44.6,43.8, 43.0, 41.0, 40.5, 40.2, 38.0, 36.5, 33.0, 30.8, 29.4, 27.5, 11.4;IR ν_(max) 3345, 1692 cm⁻¹.

(2E,3R,3aR,5aS,6aS,8R,10aR,11aS,11bR)-3a-Methyl-2-(phenylmethylene)-hexadecahydro-cyclopent[a]anthracene-3,8-dioldiacetate (28)

To a solution of compound 27 (145 mg, 0.4 mmol) in dichloromethane (10mL) was added Ac₂O (102.1 mg, 1.0 mmol), Et₃N (151.8 mg, 1.5 mmol) andDMAP (5 mg) at room temperature. After 30 min, water was added and theproduct extracted into dichloromethane (50 mL×3). Solvent was dried,filtered, and concentrated. The residue was purified by flash columnchromatography (silica gel eluted with 25% EtOAc in hexanes) to givecompound 28 (180 mg, 100%) as a white solid: ¹H NMR (CDCl₃) δ 7.39-7.09(m, 5H), 6.13 (s, 1H), 5.32 (s, 1H), 5.00 (s, 1H), 2.63 (dd, J=16.7 Hz,6.9 Hz, 1H), 2.13 (s, 3H), 1.98 (s, 3H), 0.72 (s, 3H); ¹³C NMR (CDCl₃) δ171.1, 170.6, 140.9, 137.6, 130.0, 128.2 (3C), 126.4, 123.6, 84.5, 70.1,47.8, 44.0, 43.5, 42.4, 40.6, 40.0, 37.6, 37.0, 36.9, 36.4, 30.6, 30.0,29.0, 27.9, 21.4, 21.0, 12.3; IR ν_(max) 1733, 1241 cm⁻¹.

(3S,3aR,5aS,6aS,8R,10aR,11aS,11bR)-Hexadecahydro-3,8-dihydroxy-3a-methyl-2H-cyclopent[a]anthracen-2-onediacetate (29)

Compound 28 (180 mg, 0.34 mmol) was dissolved in methanol (40 mL) andEtOAc (20 mL) and cooled to 78° C. Ozone was bubbled through thesolution for 30 min. Me₂S (5 mL) was added at 78° C. and the solutionwarmed up to room temperature for 16 h. Solvents were dried, filtered,and concentrated. The residue was purified by flash columnchromatography (silica gel eluted with 20% EtOAc in hexanes) to givecompound 29 (118 mg, 79%) as a white solid: ¹H NMR (CDCl₃) δ 5.02-5.00(m, 2H), 2.10 (s, 3H), 1.99 (s, 3H), 0.78 (s, 3H); ¹³C NMR (CDCl₃) δ210.7, 170.4, 170.1, 85.5, 69.9, 44.2, 43.9, 42.2, 42.1, 39.9, 37.6,36.8, 36.7, 36.1, 35.7, 29.8, 28.4, 27.7, 21.3, 20.5, 12.3; IR ν_(max)1762, 1734, 1240 cm⁻¹. MS (FAB) for [C₂₂H₃₂O₅+Na]⁺: 399.2147. Found:399.2159.

(3aS,5aS,6aS,8R,10aR,11aS,11bR)-8-Hydroxy-3a-methyl-hexadecahydro-2H-cyclopent[a]anthracen-2-oneacetate (30)

Freshly prepared samarium filings (225 mg, 1.5 mmol) were added to THF(5 mL) followed by iodine (273 mg, 1.0 mmol) in THF (5 mL). The mixturewas stirred under N₂ for 1 h until the mixture became a deep bluecolored solution. Compound 29 (115 mg, 0.306 mmol) in THF (9 mL) andmethanol (0.2 mL) was added. After 1 h, aqueous Na₂CO₃ (30 mL) was addedand the product was extracted into EtOAc (50 mL×3). Solvents were dried,filtered, and concentrated. The residue was purified by flash columnchromatography (silica gel eluted with 20% EtOAc in hexanes) to givecompound 30 (85 mg, 88%) as a white solid: ¹H NMR (CDCl₃) δ 5.04-5.02(m, 1H), 2.01 (s, 3H), 0.86 (s, 3H); ¹³C NMR (CDCl₃) δ 218.3, 170.4,70.0, 55.9, 50.6, 44.0, 42.3, 40.6, 40.1, 39.6, 38.9, 38.3, 38.1, 37.0,36.8, 29.9, 29.0, 27.8, 21.3, 18.1; IR ν_(max) 1736, 1243 cm⁻¹; MS (FAB)for [C₂₀H₃₀O₃+H]⁺: 319.2273. found: 319.2273.

(3aS,5aS,6aS,8R,10aR,11aS,11bR)-8-Hydroxy-3a-methyl-hexadecahydro-2H-cyclopenta[a]anthracen-2-one(31)

To a solution of compound 30 (80 mg, 0.25 mmol) in methanol (20 mL) andwater (1 mL) was added K₂CO₃ (500 mg, 3.6 mmol) at room temperature andthe reaction was refluxed for 2 h. After cooling down to roomtemperature, brine (30 mL) was added and the product was extracted intoEtOAc (50 mL×3). Solvents were dried, filtered and concentrated. Theresidue was purified by flash column chromatography (silica gel elutedwith 30% EtOAc in hexanes) to give compound 31 (62 mg, 90%) as a whitesolid: mp 145-147° C.; [α]_(D) ²⁵ +180.0 (c 0.28, CHCl₃); ¹H NMR (CDCl₃)δ 4.08-4.07 (m, 1H), 0.86 (s, 3H); ¹³C NMR (CDCl₃) δ 218.7, 66.6, 55.9,50.5, 44.1, 42.7, 40.7, 40.4, 39.9, 39.7, 38.9, 38.4, 38.0, 36.1, 32.8,29.1, 27.2, 18.2; IR ν_(max) 3436, 1741 cm⁻¹. Anal. Calcd for(C₁₈H₂₈O₂): C, 78.21; H, 10.21. Found: C, 78.26; H, 10.14.

[³⁵S]-TBPS Displacement

The IC₅₀ values for non-competitive displacers of [³⁵S]-TBPS from thepicrotoxin binding site on GABA_(A) receptors are reported in Table 1.

TABLE 1 Inhibition of [³⁵S]-TBPS Binding (nM) Compound IC₅₀ n_(Hill)MQ-74 1,190 ± 230  1.02 ± 0.15 MQ-75 226 ± 2  1.99 ± 0.30 MQ-76  574 ±142 1.04 ± 0.22 MQ-77  400 ± 118 0.88 ± 0.19 MQ-64 346 ± 33 1.13 ± 0.10MQ-65 251 ± 66 0.78 ± 0.14 MQ-81 174 ± 14 1.54 ± 0.16 MQ-82 2,680 ± 520 1.09 ± 0.16

Results presented are from duplicate experiments performed intriplicate. Error limits are calculated as standard error of the mean.Methods used are known in the art (see Jiang, X., et al., Neurosteroidanalogues. 9. Conformationally constrained pregnanes: structure-activitystudies of 13,24-cyclo-18,21-dinorcholane analogues of the GABAmodulatory and anesthetic steroids (3a,5a)- and(3a,5a)-3-hydroxypregnan-20-one. J. Med. Chem., 46: 5334-48 (2003) thecontents of which are hereby incorporated by reference in theirentirety).

Electrophysiology Results

The compounds of the present disclosure were evaluated for the abilityto potentiate chloride currents mediated by 2 μM GABA at rat α₁β₂γ_(2L)type GABA_(A) receptors expressed in Xenopus laevis oocytes and theresults are shown in Table 2.

TABLE 2 Analogue Potentiation of GABA Effects at Rat α1β2γ2GABA_(A)Receptors Expressed in Frog Oocytes Oocyte electrophysiology Com-(gating) pound 0.1 μM 1.0 μM 10 μM 10 μM MQ-74 0.80 ± 0.06 1.00 ± 0.0 3.88 ± 0.56 −0.01 ± 0.04  MQ-75 1.36 ± 0.03 7.67 ± 0.71 18.86 ± 1.99 0.13 ± 0.04 MQ-76 0.95 ± 0.20 2.08 ± 0.16 9.43 ± 0.77 0.31 ± 0.30 MQ-771.03 ± 0.10 3.65 ± 0.39 14.80 ± 1.53  0.02 ± 0.09 MQ-64 0.98 ± 0.02 2.21± 0.17 8.81 ± 1.87 0.04 ± 0.03 MQ-65 1.27 ± 0.04 2.94 ± 0.28 6.86 ± 1.340.02 ± 0.0  MQ-81 1.37 ± 0.14 5.69 ± 0.17 18.39 ± 0.70  0.09 ± 0.01MQ-82 0.80 ± 0.04 0.83 ± 0.06 2.43 ± 0.34 0.19 ± 0.17

The GABA concentration used for the control response was 2 μM. Eachcompound was evaluated on at least four different oocytes at theconcentrations indicated, and the results reported are the ratio ofcurrents measured in the presence/absence of added compound. Gatingrepresents direct current gated by 10 μM compound in the absence ofGABA, and this current is reported as the ratio of compound onlycurrent/2 μM GABA current. Error limits are calculated as standard errorof the mean (N≧4). Methods used are known in the art (see Jiang, X., etal.).

Tadpole Loss of Righting and Swimming

Table 3 discloses the anesthetic effects of the compounds of the presentdisclosure. In particular, the anesthetic effect of the compounds of thepresent disclosure on Loss of Righting Reflex (LRR) and Loss of SwimmingReflex (LSR).

TABLE 3 Tadpole Loss of Righting (LRR) & Loss of Swimming (LSR) EC₅₀Values (μM) Reflexes by Analogues Com- Tadpole LRR Tadpole LRR TadpoleLSR Tadpole LSR pound EC₅₀ (μM) n_(Hill) EC₅₀ (μM) n_(Hill) MQ-74 3.22 ±0.03 −15.6 ± 1.8  >10 — MQ-75 0.26 ± 0.04 −1.71 ± 0.42 0.95 ± 0.0  −15.9± 0.5 MQ-76 0.39 ± 0.01 −2.31 ± 0.08 1.73 ± 0.03 −36.3 ± 0.1 MQ-77 0.59± 0.07 −1.84 ± 0.31 1.73 ± 0.04 −36.4 ± 0.1 MQ-64 3.08 ± 0.01 −15.5 ±1.0  None — MQ-65 2.09 ± 0.12 −2.42 ± 0.24 5.48 ± 0.02 −33.2 ± 0.2 MQ-810.77 ± 0.04 −2.94 ± 0.28 1.73 ± 0.04 −36.4 ± 0.1 MQ-82 3.11 ± 0.01 −15.6± 1.1  7.93 ± 0.0  −27.0 ± 0.0

Methods used are known in the art (see Jiang, X., et al.). Error limitsare calculated as standard error of the mean (N=10 or more animals ateach of five or more different concentrations).

General Methods

The compounds discussed in the present disclosure were produced asdiscussed elsewhere throughout this disclosure and by the followingmethods.

Solvents were either used as purchased or dried and purified by standardmethodology. Extraction solvents were dried with anhydrous Na₂SO₄ andafter filtration, removed on a rotary evaporator. Flash chromatographywas performed using silica gel (32-63 μm) purchased from ScientificAdsorbents (Atlanta, Ga.). Melting points were determined on a Koflermicro hot stage and are uncorrected. FT-IR spectra were recorded asfilms on a NaCl plate. NMR spectra were recorded in CDCl₃ at ambienttemperature at 300 MHz (¹H) or 74 MHz (¹³C). Purity was determined byTLC on 250 μm thick Uniplates™ from Analtech (Newark, Del.). All purecompounds (purity>95%) gave a single spot on TLC. Elemental analyseswere performed by M-H—W Laboratories (Phoenix, Ariz.).

EQUIVALENTS AND SCOPE

In view of the above, it will be seen that the several advantages of thedisclosure are achieved and other advantageous results attained. Asvarious changes could be made in the above processes and compositeswithout departing from the scope of the disclosure, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

When introducing elements of the present disclosure or the variousversions, embodiment(s) or aspects thereof, the articles “a”, “an”,“the” and “said” are intended to mean that there are one or more of theelements. It is also noted that the terms “comprising”, “including”,“having” or “containing” are intended to be open and permits theinclusion of additional elements or steps.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R₁ is H, ═O,═CHCN, ═CHCO₂R_(z), where R_(z) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, β-CN, β-OH, β-OR_(y), where R_(y) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, or C(O)R_(x), where R_(x)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; R₂ is H, ═O, ═CHCN,═CHCO₂R_(w), where R_(w) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, β-CN, β-OH, β-OR_(v), where R_(v) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, or C(O)R_(u), where R_(u)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; R₃ is H, ═O, ═CHCN,═CHCO₂R_(t), where R_(t) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl, —CN, β-OH, β-OR_(s), where R_(s) is optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, or C(O)R_(r), where R_(r)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; R₄ is H, optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl; R₅ is H, ═O, NH(CH₃)₂,NH(CH₂CH₃)₂, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CO₂R_(q), where R_(q) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, CH₂OR_(p), where R_(p) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, C(O)R_(o), where R_(o) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, C(O)NHR_(n), where R_(n) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, CH₂NHR_(m), where R_(m) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, or OR_(l) where R_(l) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl; R₆ is H, optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl; R₇ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl; R₈ is H, optionally substituted morpholinyl, or OR_(k), whereR_(k) is optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl; R₉ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl; R₁₀ is H, CH₂N(CH₃)₂,CH₂N(CH₂CH₃)₂, CO₂R_(j), where R_(j) is optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, optionally substitutedC₂-C₄ alkynyl, or optionally substituted aryl, CH₂OR_(i), where R_(i) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, C(O)R_(h), where R_(h) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, C(O)NHR_(g), where R_(g) isoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl, or CH₂NHR_(f), where R_(f) is optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl, R₁₁ is H or C(O)R_(e), whereR_(e) is optionally substituted C₁-C₂₀ alkyl, optionally substitutedC₂-C₂₀ alkenyl, or optionally substituted C₂-C₂₀ alkynyl; and, - - -denotes an optional, additional C—C bond, resulting in either a C═C bondbetween, C₁-C₂, C₂-C₃, C₆-C_(6a), C_(6a)-C₇, or C₉-C₁₀, with theprovisos that when present between: (i) C_(6a)-C₇, R₇ is not present;(ii) C₆-C_(6a), R₇ is not present and either R₅ or R₆ is not present,and, when present, R₅ is other than ═O; (iii) C₁-C₂, R₁ is other than═O, ═CHCN or ═CHCO₂R_(z), and R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w);and, (iv) C₂-C₃, R₂ is other than ═O, ═CHCN or ═CHCO₂R_(w), and R₃ isother than ═O, ═CHCN or ═CHCO₂R_(t).
 2. The compound of claim 1, whereinR₁₁ is H.
 3. The compound of claim 1, wherein R₃ is ═O.
 4. The compoundof claim 1, wherein R₃ is spiroepoxy.
 5. The compound of claim 1,wherein R₃ is β-CN.
 6. The compound of claim 1, wherein R₁, R₂, R₅, R₆,R₈, R₉, and R₁₀ are H.
 7. The compound of claim 1, wherein R₄ is methyl.8. The compound of claim 1, wherein R₇ is H.
 9. The compound of claim 8,wherein R₇ is in the alpha configuration.
 10. The compound of claim 1,wherein a double bond is present between C₂-C₃.
 11. The compound ofclaim 10, wherein R₃ is CN.
 12. The compound of claim 1, having thestructure (I-a):

wherein R₃ is ═O, ═CHCN, ═CHCO₂R_(t), where R_(t) is optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl, —CN, β-OH, β-OR_(s), where R_(s)is optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl, β-NO₂, spiroepoxy, orC(O)R_(r), where R_(r) is optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;and, - - - denotes an optional C—C bond, resulting in a C═C bond betweenC₂-C₃ with the proviso that when present, R₃ is other than ═O, ═CHCN or═CHCO₂R_(t).
 13. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 having the structure:

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising the compound of claim 1, a pharmaceuticallyacceptable salt thereof, or a combination of two or more thereof, and apharmaceutically acceptable carrier.
 18. A method of inducing anesthesiain a subject in need thereof, said method comprising administering tothe subject a therapeutically effective amount of the compound of claim1, or a pharmaceutically acceptable salt thereof.
 19. A method fortreating disorders related to GABA function in a subject in needthereof, said method comprising administering to the subject atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 20. The method of claim 19,wherein the disorder is selected from the group consisting of insomnia,mood disorders, convulsive disorders, Fragile X syndrome, anxiety, orsymptoms of ethanol withdrawal.